Biomedical Engineering Reference
In-Depth Information
I
ZnCl
t
-BuLi (2 equiv)
Et
2
O, -110°C
then ZnCl
2
(1 equiv)
THF, -110°C to rt
OBn
176
OBn
2 steps
N
N
172
Pd(PPh
3
)
4
(10 mol%)
Benzene, rt
60%
71%
H
OTBDMS
H
OTBDMS
177
175
I
N
H
OTBDMS
174
O
O
I
Zn
ZnCl
2
(1 equiv)
THF, -90°C
O
O
179
N
N
2 steps
173
then
t
-BuLi (3 equiv)
-90°C to rt
Pd(PPh
3
)
4
(10 mol%)
Benzene, rt
51%
70%
H
OTBDMS
H
OTBDMS
178
180
SCHEME 2.43
Synthesis of (+)-pumiliotoxins A and B.
OTBDPS
t
-BuLi (2 equiv)
Et
2
O, -78°C
then ZnCl
2
(1 equiv)
THF, -78°C to rt
28%
ZnCl
179
OTBDPS
(a)
OTBDPS
O
Pd(PPh
3
)
4
(10 mol%)
Benzene, rt
182
I
OTBDPS
O
ZnCl
2
(1 equiv)
THF, -90°C
181
(b)
183
Zn
then
t
-BuLi (3 equiv)
-90°C to rt
55%
184
SCHEME 2.44
Feasibility study in the synthesis of (+)-pumiliotoxin B.
, a preliminary study
showed that a Negishi cross-coupling carried out using the organic zinc chloride
Interestingly, for the synthesis of (
þ
)-pumiliotoxin B
173
182
afforded the coupled product
in a modest yield of 28%, together with a complex
mixture of unidentifiable compounds, probably due to the decomposition of the
isopropylidene acetal group in the presence of Lewis acidic zinc halide. The use of
dialkylzinc derivative
183
184
was more encouraging, leading to the cross-coupled
product in 55% yield (Scheme 2.44). With these reaction conditions in hand, the
advanced intermediate
180
used for the synthesis of (
þ
)-pumiliotoxin B
173
could be
obtained as a single (
E
)-isomer in 51% yield (Scheme 2.43).
2.2.4.3.
is a natural product that is effec-
tive against methicillin-resistant
S. aureus
(MRSA) and vancomycin-resistant
Enterococcus
(VRE), showing also significant level of cytotoxicity against several
cell lines (Figure 2.14) [94]. The structure presents a 2-deoxy-sugar unit anchored to
the polycyclic system through a tertiary
Lactonamycin Lactonamycin
185
-keto-glycosidic bond, a naphto[
e
]isoindole
ring (EF rings), and a fused perhydrofuran-furanone ring system (AB rings).
Different groups have reported the synthesis of CDEF model system toward the
synthesis of lactonamycin
a
, but only one uses the Negishi cross-coupling to
assemble the EF ring with the C ring [95] (Figure 2.14).
185
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